HMR-1883, A NOVEL CARDIOSELECTIVE INHIBITOR OF THE ATP-SENSITIVE POTASSIUM CHANNEL - PART II - EFFECTS ON SUSCEPTIBILITY TO VENTRICULAR-FIBRILLATION INDUCED BY MYOCARDIAL-ISCHEMIA IN CONSCIOUS DOGS

The activation of the ATP-sensitive potassium channel (K-ATP) during m yocardial ischemia leads to potassium efflux, reductions in action pot ential duration and the formation of ventricular fibrillation (VF). Dr ugs that inactivate K-ATP should prevent these changes and thereby pre vent VF. However, most K-ATP antagonists also alter pancreatic channel s, which promote insulin release and hypoglycemia. Recently, a cardios elective K-ATP antagonist, HMR 1883, has been developed that may offer cardioprotection without the untoward side effects of existing compou nds. Therefore, VF was induced in 13 mongrel dogs with healed myocardi al infarctions by a 2-min coronary artery occlusion during the last mi nute of a submaximal exercise test. On subsequent days, the exercise-p lus-ischemia test was repeated after pretreatment with HMR 1883 (3.0 m g/kg i.v., n = 13) or glibenclamide (1.0 mg/kg i.v., n = 7). HMR 1883 (P < .001) and glibenclamide (P < .01) prevented VF in 11 of 13 and 6 of 7 animals, respectively. Glibenclamide, but not HMR 1883, elicited increases in plasma insulin and reductions in blood glucose. Glibencla mide also reduced (P < .01) both mean coronary blood flow and left ven tricular dP/dt maximum as well as the reactive hyperemia induced by 15 -sec coronary occlusions (-30.3 +/- 11%), whereas HMR 1883 did not alt er this increase in coronary flow (-3.0 +/- 4.7%). Finally, myocardia[ ischemia (n = 10) significantly (P < .01) reduced refractory period ( control, 121 +/- 2 msec; occlusion, 115 +/- 2 msec), which was prevent ed by either glibenclamide or HMR 1883. Thus, the cardioselective K-AT P antagonist HMR 1883 can prevent ischemically induced reductions in r efractory period and VF without major hemodynamic effects or alteratio ns in blood glucose levels. These data further suggest that the activa tion of K(ATP)s may play a particularly important role in both the red uctions in refractory period and lethal arrhythmia formation associate d with myocardial ischemia.